NKT cells are CD1d-restricted immunoregulatory T cells that bridge between innate and adaptive immunity. Two subsets of NKT cells have been identified, invariant NKT (iNKT) cells that express an invariant V?14-J?18 TCR ? chain and variant NKT (vNKT) with a more diverse TCR repertoire. iNKT cells have been extensively studied, playing an important role in autoimmune disease, infection and tumor immunity. Their early response and rapid secretion of both TH1 and TH2 cytokines, as well as lack of memory response, highlights the innate-like function of these cells. The activation and function of vNKT cells, on the other hand, remain relatively unexplored. This proposal seeks to compare and contrast the diversity and function of both iNKT and vNKT cells in response to altered CD1d expression and allelic differences in CD1d as well as determine the molecular mechanisms governing selection and development of these cell types. First, we will use spontaneous liver pathology in CD1d transgenic mice to examine whether and how altered CD1d expression pattern affects the function of both iNKT and vNKT cells. We will also explore how downstream effects of this altered function result in the spontaneous chronic liver disease. Secondly, we will use CD1 congenic mice as a model to study the diversity, antigen presentation requirements, and potential memory response of vNKT cells as compared to iNKT cells. Thirdly, we will use Elf-1-deficient mice, which are selectively impaired in NKT cell development, as a model to study how ETS family transcription factors may regulate the development and function of NKT cells. As both subsets of NKT cell are present in humans, our studies on the development, regulation and function of these unique T cell populations will provide a better understanding of the comparative contributions of these cell types in normal and pathological immune responses.